Investigation has focused on the properties and regulation of corticotropin releasing factor (CRF) receptors and the mechanisms of interaction between CRF and other regulators of ACTH secretion, with emphasis on adaptation to stress. A. CRF receptors and pituitary-adrenal responses during stress. Previous studies have shown that the biphasic ACTH responses to prolonged immobilization are accompanied by decreases in pituitary CRF receptors and hypersensitivity of the pituitary to CRF infusion and a second novel stress. Extension of these studies using a more mild form of stress, intermittent immobilization for 2.5 hr daily, showed complete desensitization of the ACTH response after the first 4 days of immobil- ization, while plasma glucocorticoids were markedly increased. Despite a decrease in pituitary CRF receptors, ACTH responses to a novel stress, but not to CRF infusion, were enhanced. These responses were similar to those observed in types of human depression in which hypercortisolemia is a characteristic feature. CRF receptors in the intermediate pituitary were unchanged during immobilization stress. In contrast to the changes during immobilization stress, CRF receptors were unaltered in the anterior pituitary during cold stress, but were markedly increased in the intermediate lobe. B. CRF receptor properties and coupling to cellular function. The binding characteristics of CRF receptors determined in membranes from the neurointermediate lobes were almost identical to those in the anterior pituitary. Analysis of the solubilized cross-linked CRF-receptor complex in different target tissues by gel electrophoresis showed similar properties in both pituitary lobes, with a molecular weight of about 70 kDa. It is known that CRF receptor occupancy results in activation of adenylate cyclase. In addition, experiments showing that pharmacological inhibition of protein kinase C inhibits ACTH release suggest that the CRF receptor may be also linked to a calcium/phospholipid-dependent transduction system.